DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The application is a 371 application, filed 09/06/2024, of PCT application PCT/EP2023/055796, filed 03/07/2023, which claims priority benefits from Foreign Application No. GB2203250.2, filed 03/09/2022. The effective filing date of this application is 03/09/2022, the filing date of Foreign Application No. GB2203250.2.
Claim Status
Amendments dated 09/06/2024 are entered.
Claims 1-22 and 25-27 are pending and under examination.
Information Disclosure Statement
The IDS submitted 09/06/2024 is being considered.
Drawings
The drawings are objected to because:
In Figures 1-3, the light gray square and dark gray squares are both labeled as D-GlcpNAc (i.e. glucose). Should the light gray square be D-GalNAc or D-GalpNAc (i.e. galactose) to be consistent with the teachings of the specification?
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
The file name on record is “70133US01_SL_filed_6Sep2024.xml”, the date of creation is 09/06/2024, and the file size is 48229 bytes, which do not match the information in the Sequence Incorporation by Reference paragraph in the amended specification.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Objections
Claims 1, 3, 5-7, 16, and 17 are objected to because of the following informalities:
First, claim 1 contains a grammatical and punctuation errors. The claim may be fixed by reciting:
“…a genetically modified Neisseria gonorrhoeae bacterium, wherein said bacterium comprising…” and
“…non-phase variable, thus resulting in…”.
Secondly, claim 1 should recite the full name of the abbreviation “Hep I” for its first instance of recitation and place “Hep I” in parenthesis after the full name if this abbreviation is to be used thereafter in place of the full name.
Claim 3 requires a comma after “locks expression ON” and a comma after “locks expression OFF” for proper punctuation.
Claim 5 requires deletion of “either” if there are more than two options to choose from for grammatical consistency.
Claim 6 is suggested to recite “comprise one or more of lgtA, lgtC, lgtD, and/or lgtG” to remove ambiguity of what the “more” refers to. This also encompasses the option of all the genes, so “all” can be deleted.
Claim 7 requires a comma after “locked ON” and a comma after “locked OFF” for proper punctuation.
In claim 16, the symbols “à” should be “→” according to the specification. Appropriate correction is required.
Claim 17 should recite the full name of the abbreviation “Hep II” for its first instance of recitation and place “Hep II” in parenthesis after the full name if this abbreviation is to be used thereafter in place of the full name.
Claim Interpretation
In claim 11, “substantially” is interpreted as defined in paragraph [000109] on page 26 of the specification.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-22 and 25-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claims 1, 11, 14 recite the broad recitation “at least four hexose monosaccharides”, and the claims also recite “(4Hex or 5Hex)” which is the narrower statement of the range/limitation.
Claims 2, 12, 13 recite the broad recitation “less than four hexose monosaccharides”, and the claims also recite “(2Hex or 3Hex)” which is the narrower statement of the range/limitation.
Claim 17 recites the broad recitation “comprises its beta-oligosaccharide chain”, and the claim also recites “(4HexG+ or 5HexG+)” which is the narrower statement of the range/limitation.
Furthermore, claims 17 and 18 recite the broad recitation “does not comprise its beta-oligosaccharide chain”, and the claims also recite “(4HexG- or 5HexG-)” which is the narrower statement of the range/limitation.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The dependent claims do not resolve the indefiniteness of their parent claim(s), and therefore inherit the indefiniteness of their parent claim(s).
Further regarding claims 1, 2, and 11-14, the parenthetical limitations “(4Hex or 5Hex)” or “(2Hex or 3Hex)” render the claim indefinite because it is unclear whether the limitation(s) in the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claims 17-18, the parenthetical limitations “(4HexG- or 5HexG-)” and/or “(4HexG+ or 5HexG+)” render the claim indefinite because it is unclear whether the limitation(s) in the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
The dependent claims do not resolve the indefiniteness of their parent claim(s), and therefore inherit the indefiniteness of their parent claim(s).
Further regarding claims 1-3, 7, and 8, the recitation of “genetic modification(s)” encompasses one and more than one genetic modification. However, although “genetic modification(s)” is defined in the instant Specification (p. 8, para. 00054), it is still unclear what constitutes one genetic modification. The Specification defines “genetic modification(s)” as any alteration to genetic material to provide a specified effect (e.g. changing the expressing pattern of a gene or gene(s)). Does this mean that one genetic modification effects only one gene or can one genetic modification effect more than one gene? The indefiniteness arises because the disclosure only teaches methods of achieving both required limitations (a) and (b) with more than one mutation, affecting more than one genes, but the claims encompass using only one genetic modification to achieve both limitations. It is thus unclear if the commonly understood possible interpretation of “genetic modification” based on the definition of “genetic modification(s)” provided in the Specification means one mutation that affects one gene, because it would conflict with the teachings of the Specification regarding the number of modifications required to achieve the claimed limitations. If the Applicant does not intend to encompass one genetic modification, the indefiniteness can be resolved by removing this possibility by replacing “genetic modification(s)” with “genetic modifications”.
The dependent claims do not resolve the indefiniteness of their parent claim(s), and therefore inherit the indefiniteness of their parent claim(s).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 13 recites the function of mAb L1 and mAb 4C4 and a result that would flow from this function. It tells how the immunogenic composition can be characterized but does not actually further limit the immunogenic composition more than its parent claims. Even if the mAb binding patterns were re-written to distinctly be characteristic of the immunogenic composition, it would be a result that would naturally flow from the product already arrived at in claim 12 since they meet the structural requirements that limit the binding of the claimed antibodies and therefore would exhibit the claimed binding pattern (see the 35 U.S.C. 103 rejection regarding claim 13 for further explanation). One suggestion would be to move the limitations of current claim 13 into claim 12 to define the method of determining “no detectable OMVs” instead of keeping claim 13 as a dependent claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-10, 11-14, 16-22, and 25-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chakraborti (Chakraborti et al, Phase-Variable Heptose I Glycan Extensions Modulate Efficacy of 2C7 Vaccine Antibody Directed against Neisseria gonorrhoeae Lipooligosaccharide, published 2016) in view of Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (Zhou et al, Hexa-Acylated Lipid A Is Required for Host Inflammatory Response to Neisseria gonorrhoeae in Experimental Gonorrhea, published 2014) and Baker (Baker et al, Microbial biosynthesis of designer outer membrane vesicles, published 2014).
Regarding claim 1, Chakraborti teaches a genetically modified Neisseria gonorrhoeae bacterium comprising genetic modifications that
render the phase variability of at least one lgt gene non-phase variable (Abstract) to arrive at LOS glycan structures comprising of four or five hexose monosaccharides elongating from Hep I (i.e. the alpha chain, which is the chain that elongates from Hep I as defined in the instant Specification, para. 00067) (Chakraborti, Figure 1 A and B).
Chakraborti does not explicitly teach an immunogenic composition comprising isolated gonococcal outer membrane vesicles (OMVs) obtained or obtainable from a genetically modified Neisseria gonorrhoeae, modified according to the above genetic modifications.
Chakraborti does not explicitly teach detoxifying the LOS.
However, Biemans teaches an immunogenic composition comprising isolated gonococcal outer membrane vesicles (OMVs) obtained or obtainable from a genetically modified neisserial (preferably meningococcal) strain of bacterium, wherein said bacterium comprises genetic modifications that
render the phase variability of at least one lgt gene non-phase variable (p. 5, lines 11-18), and
detoxify the LOS, e.g. by deactivating the lpxL1 gene (p. 12, lines 11-22).
Biemans teaches this immunogenic composition as a vaccine against Neisseria meningitidis (meningococcus) because it addresses the issues that (a) phase-variable LOS antigen presentation and (b) toxicity of LOS confer on the use of LOS as the basis of vaccines against Neisseria meningitidis (p. 5, lines 11-18 and p. 12, lines 11-22). Chakraborti teaches the same issues exist for Neisseria gonorrhoeae, and specifically teaches the non-phase variable LOS antigen presentation version for Neisseria gonorrhoeae. As evidenced by Zhou, Neisseria gonorrhoeae also contains an LOS structure that can also be detoxified in the same way taught by Biemans for Neisseria meningitidis, i.e. inactivation of the lpxL1 gene leads to a penta-acylated lipid A replacing the originally hexa-acylated lipid A (Abstract).
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to use a known technique to improve similar products in the same way (see MPEP 2143(I)(C)). Specifically, it would have been obvious to apply the known technique of making an immunogenic composition comprising OMVs comprising of LOS glycan structures with four or five hexose monosaccharides, resulting from non-phase variable lgt genes, matching the claimed limitations, except obtained from genetically modified Neisseria meningitidis to treat Neisseria meningitidis-mediated pathologies, as taught by Biemans, towards the of LOS glycan structures with four or five hexose monosaccharides, resulting from non-phase variable lgt genes, obtained from genetically modified Neisseria gonorrhoeae, taught by Chakraborti, to treat Neisseria gonorrhoeae-mediated pathologies
It would have also been obvious to detoxify the LOS of Neisseria gonorrhoeae in the same way and for the same motivations provided by Biemans for developing a vaccine against Neisseria meningitidis, and would have reasonable expectation of success, since the detoxification method taught by Biemans is also applicable to Neisseria gonorrhoeae, as evidenced by the gene-function correlation taught by Zhou et al.
One skilled in the art, before the effective filing date of the instant application, would be motivated to develop the Neisseria gonorrhoeae epitopes taught by Chakraborti into an immunogenic composition comprising of OMVs that already properly display these epitopes for use as a vaccine composition against Neisseria gonorrhoeae. One would be motivated to further develop the immunogenic composition with non-phase variable displayed epitope to ensure that the epitope site is always available to stimulate an immune response, solving the issue of naturally variably displayed epitopes that can help antigens evade the immune system. One would be motivated to further detoxify the LOS to prevent unwanted systemic toxicity that could cause adverse effects on the subject and/or detract from the desired antigen-specific immune response.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success that the genetically modified Neisseria gonorrhoeae from Chakraborti could also produce OMVs exhibiting the engineered structures since OMV vesiculation is a process ubiquitous to all Gram-negative bacteria, as evidenced by Baker, which includes Neisseria gonorrhoeae. It would be reasonably expected that the OMV derived from the genetically modified Neisseria gonorrhoeae would exhibit the claimed structures associated with the genetic changes.
Claims 2-10, 12-14, 16-22, and 25-27 depend on claim 1. The teachings of the references regarding the parent claim(s) are incorporated in its entirety for the appropriate dependent claim(s) and discussed further below, as is relevant for each claim.
Regarding claims 2, 7, 12, and 13, Chakraborti further teaches genetic modifications lgtA(+) (i.e. locked on), resulting in lgtA being constitutively expressed, and the combination of lgtA(+) lgtD(+), with both options comprising of lgtC(-) (i.e locked off), resulting in lgtC losing expression, both rendering the bacterium incapable of producing OMBs displaying LOS glycan structures with less than four hexose monosaccharides elongating from Hep I (Figure 1B). Claim 13 depends on claim 12. The teachings of the references regarding claim 12 are incorporated in its entirety for claim 13 and discussed further. Further regarding claim 13, the instant specification discloses the epitopes and structural requirements of mAb L1 and mAb 4C4 (p. 24 Table 2). Additionally, Chakraborti teaches absence of LOS glycan structures having less than four hexose monosaccharides elongating from Hep I leads to absence of mAb L1 binding (Figure 1B, L1 row). Additionally, Chakraborti teaches absence of LOS glycan structures having less than four hexose monosaccharides elongating from Hep I leads to absence of mAb L8, which has the same structural requirements as instantly claimed mAb 4C4 in that Hep I extension beyond Gal-Glc-Hep I abrogates binding, (Figure 1B, L8 row).
Regarding claim 8, the motivations for and reasonable expectation of success of combining detoxifying the LOS, as taught by Biemans, in the base structure taught by Chakraborti is previously discussed for claim 1. Biemans further teaches a specific method to detoxify the LOS genetically by inactivation of genes involved in Lipid A biosynthesis by downregulating the msbB and/or htrB genes (p. 12, lines 11-18), which are also called lpxL1 and lpxL2, respectively (p. 12, line 21). As evidenced by Zhou and previously explained for claim 1, this strategy is applicable to Neisseria gonorrhoeae.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to detoxify the LOS of Neisseria gonorrhoeae in the same way and for the same motivations provided by Biemans for developing a vaccine against Neisseria meningitidis.
One skilled in the art, before the effective filing date of the instant application, would be motivated to genetically detoxify the LOS to create a permanent detoxified structure, and do so specifically by targeting the lpxl1 gene or lpxl1 protein since this is a known gene and protein that detoxifies the LOS but can be removed without causing unwanted effects to the desired immunogenicity of the antigen.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since the detoxification method taught by Biemans is also applicable to Neisseria gonorrhoeae, as evidenced by the gene-function correlation taught by Zhou et al.
Regarding independent claim 11, Biemans teaches an immunogenic composition substantially comprising isolated OMVs (from Neisseria meningitidis) that display LOS glycan structures having four or five hexose monosaccharides (Figure 2). Further, as explained for claim 8, Biemans teaches LOS can be detoxified genetically by inactivation of genes involved in Lipid A biosynthesis by downregulating the msbB and/or htrB genes (p. 12, lines 11-18), which are also called lpxL1 and lpxL2, respectively (p. 12, line 21).
Regarding independent claim 11, Chakraborti also teaches an immunogenic composition substantially comprising isolated OMVs (from Neisseria gonorrhoeae) that display LOS glycan structures having four or five hexose monosaccharides (e.g. Figure 1A and 1B, silver stain and 3F11 antibody row).
The teachings, motivation, and likelihood of success of how to arrive at the claimed immunogenic composition from these two references are previously discussed for claim 1 and claim 8, and are applicable and incorporated here for claim 11, which is more general than claim 1, except it distinctly limits the lipid A structure in the detoxified LOS, similarly to claim 8.
Biemans and Chakraborti do not explicitly teach the LOS comprises a pentaacylated lipid A rather than a hexaacylated lipid A.
The particular method for detoxifying by inactivation of lpxL1 or lpxL1 is previously discussed in claim 8 and incorporated here. Claim 11 only recites the structural effect, generating a pentaacylated lipid A, of the mutation of claim 8 that leads to the detoxification of the LOS. However, as evidenced by Zhou, inactivation of the lpxL1 (also known as msbB) gene in Neisseria gonorrhoeae, as previously arrived at for claims 1 and 8, would result in a penta-acylated lipid A instead of the hexa-acylated lipid A phenotype (Abstract), which as explained for claims 1, and specifically for lpxL1 in claim 8, detoxifies the LOS, which is desirable in preventing systemic adverse effects on the subject which can detract the immune system from the desired antigen-specific immune response.
Claims 12 and 13 also depend on claim 11 (in addition to depending on claim 1). The teachings of the references regarding claim 11 are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claim 12, Chakraborti further teaches genetic modifications lgtA(+) (i.e. locked on) and the combination of lgtA(+) lgtD(+), with both options comprising of lgtC(-) (i.e locked off) both render the bacterium incapable of producing OMBs displaying LOS glycan structures with less than four hexose monosaccharides elongating from Hep I (e.g. Figure 1B, silver stain row). Regarding claim 13, the claimed limitations are results that would naturally flow from the product already arrived at in claim 12 since they meet the structural requirements that limit the binding of the claimed antibodies and therefore would exhibit the predicted binding pattern. The instant specification discloses the epitopes and structural requirements of mAb L1 and mAb 4C4 (p. 24 Table 2). Additionally, Chakraborti teaches absence of LOS glycan structures having less than four hexose monosaccharides elongating from Hep I leads to absence of mAb L1 binding (Figure 1B, L1 row). Additionally, Chakraborti teaches absence of LOS glycan structures having less than four hexose monosaccharides elongating from Hep I leads to absence of mAb L8, which has the same structural requirements as instantly claimed mAb 4C4 in that Hep I extension beyond Gal-Glc-Hep I abrogates binding, (Figure 1B, L8 row).
Regarding claim 3, Chakraborti further teaches that the lgt loci required for HepI variation (lgtA, lgtC, and lgtD) were genetically locked on or off in different combinations (Abstract), which leads to the gene being constitutively expressed or losing expression, respectively.
Claims 4 and 5 depend on claim 3. The teachings of the references regarding the parent claim(s) are incorporated in its entirety for the appropriate dependent claim(s) and discussed further below, as is relevant for each claim.
Regarding claim 4, Chakraborti further teaches lgt loci were locked on by mutating the repetitive homopolymeric sequence, known as the homopolymeric tract, found in each gene such that the homopolymer was removed but the coding sequence was not altered (p. 4579, col. 2, para. 1). Regarding claim 5, Chakraborti further teaches the lgt loci were locked off by deletion, insertional inactivation, or by inserting stop codons within the reading frames (p. 4579, col. 2, para. 1 – p. 4580, col. 1, para. 1).
Regarding claim 6, Chakraborti further teaches the lgt genes comprise of lgtA, lgtC, lgtD, and lgtG (e.g. Figure 1B).
Regarding claims 9 and 19, Chakraborti further teaches that reduction modifiable protein (rmp) is a conserved antigen on Neisseria gonorrhoeae that elicits nonprotective and subversive host immune responses, listing rmp in the list of antigens that pose an obstacle to gonococcal vaccine development (p. 4576, col. 2, para. 2).
Biemans and Chakraborti do not explicitly teach a further genetic modification which decreases or abolishes expression and/or function of the rmp gene, rmp mRNA, and/or rmp polypeptide, leading to OMVs that comprise reduced or no detectable levels of the rmp polypeptide.
However, it would have been obvious to one skilled in the art, before the effective filing date of the instant application, to deactivate this identified problematic antigen gene that will not lead to a beneficial immune response against the pathogen, because it is contrary or unnecessary for a vaccine meant to stimulate an immune response to a recognizable antigen. It follows that reducing or deactivating the gene’s expression would result in low or no detectable levels of the polypeptide.
One skilled in the art, before the effective filing date of the instant application, would be motivated to remove this antigen known to induce a response contrary to the purpose of a vaccine.
One skilled in the art, before the effective filing date of the instant application, would have reasonable expectation of success since the LOS still comprises of immunogenic antigens (i.e. from the lgt gene combinations) but without the unnecessary and subversive rmp antigen.
Claim 10 depends on any preceding claim, claims 1-9. The teachings of the references regarding these preceding claims are incorporated in its entirety for claim 10 and discussed further below, as is relevant.
Regarding claim 10, Chakraborti further teaches the genetically modified Neisseria gonorrhoeae bacteria mutants are derived from strain MS11 (p. 4577, col. 1, section: Construction of mutants, para. 1; p. 4579, Table 1; and information about the strain on p. 4577, col. 1, section: Bacterial strains and culture conditions, para. 1).
Regarding claim 14, Chakraborti further teaches an immunogenic composition wherein over 80% of the OMVs display LOS glycan structures comprising four or five hexose monosaccharides (e.g. Figure 1A and 1B, silver stain row).
Regarding claim 16, Chakraborti further teaches the four and five hexose monosaccharide chains elongating from Hep I are the instantly claimed chains (p. 4578, Figure 1A and 1B).
Regarding claim 17, Chakraborti further teaches the LOS glycan structures comprise Hep II, which either comprises its beta-oligosaccharide chain (p. 4578, Figure 1A and Figure 1B, mutants 5-Hex/G+ and 4-Hex/G+) or does not comprise its beta-oligosaccharide chain (p. 4578, Figure 1A and Figure 1B, mutants 5-Hex/G- and 4-Hex/G-).
Claim 18 depends on claim 17. The teachings of the references regarding claim 17 are incorporated in its entirety for claim 18 and further discussed.
Regarding claim 18, Chakraborti further teaches Hep II does not comprise its beta-oligosaccharide chain (p. 4578, Figure 1A and Figure 1B, mutants 5-Hex/G- and 4-Hex/G-).
Regarding claim 20, Biemans further teaches the immunogenic composition further comprising a pharmaceutically acceptable excipient (p. 23, lines 1-2).
Regarding claim 21, Biemans further teaches the immunogenic composition further comprising a suitable adjuvant, such as an aluminum salt, such as aluminum phosphate and preferably aluminum hydroxide (p. 20, lines 19-22).Regarding claim 22, Biemans further teaches a vaccine comprising the immunogenic composition (e.g. p. 19, lines 26-30).
Claims 25 and 26 depend on claim 22. Claim 27 depends on claims 1 and 22. The teachings of the references regarding the parent claim(s) are incorporated in its entirety for the dependent claims and discussed further below, as is relevant for each claim.
Regarding claims 25-27, Biemans teaches the immunogenic composition or vaccine (which comprises of the immunogenic composition) is used for the treatment or prevention of neisserial disease, wherein the process allows the vaccine to be of reduced toxicity and induce a T cell-dependent bactericidal response against LOS (i.e. an immune response). Biemans teaches this method preferably for treating or preventing against meningococcal disease or immunizing against N. meningitidis. However, as presented previously, Chakraborti teaches that the same issues with vaccine development due to phase variable OMV structures exists in N. gonorrhoeae and teach the immunogenic composition that could also be used to immunize, treat, and prevent against N. gonorrhoeae diseases.
It would have been obvious to one skilled in the art, before the effective filing date of the instant application, to formulate the immunogenic composition with other components needed to make a stable, safe, and effective vaccine, such as pharmaceutically acceptable excipients and commonly used vaccine adjuvants. It would have been obvious to one skilled in the art, before the effective filing date of the instant application, that using the previously described antigens derived from N. gonorrhoeae instead of N. meningitidis would treat, prevent, immunize, and/or raise an immune response against N. gonorrhoeae more specifically than if the antigens were derived from a different species.
One skilled in the art, before the effective filing date of the instant application, would be motivated to develop a vaccine with antigens derived from N. gonorrhoeae, and add further excipients and adjuvants to help stabilize and boost the immunogenicity of the antigen, for the advantage of eliciting an immune response that targets N. gonorrhoeae with a reasonable expectation of success since known antibodies against these antigens are shown to bind them, as shown in Chakraborti.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chakraborti (Chakraborti et al, published 2016) in view of Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014), as applied to claim 1 above, and further evidenced by Saha (Saha et al, Lipid A heterogeneity and its role in the host interactions with pathogenic and commensal bacteria, published 2022).
Claim 15 depends on claim 1. The teachings of the references regarding parent claim 1 and related claim 8, directed to limitations to detoxifying the LOS, are incorporated in its entirety for claim 15 and discussed further below, as is relevant for each claim.
Regarding claim 15, as previously discussed for claim 8, Biemans further teaches LOS can be detoxified genetically by inactivation of genes involved in Lipid A biosynthesis by downregulating the msbB and/or htrB genes (p. 12, lines 11-18), which are also called lpxL1 and lpxL2, respectively (p. 12, line 21).
As evidenced by Saha, lpxL1 deletion would result in an LOS that lacks the second lauroyl chain from the non-reducing end of the GlcN disaccharide in Neisseria meningitidis (Figure 1B). In other words, claim 15 recites the product achieved by modifications in claim 8.
It would have been evident to one skilled in the art that as the lpxL1 gene is conserved between Neisseria meningitidis and Neisseria gonorrhoeae, as evidenced by Zhou, its function would also be conserved and therefore, its deletion in Neisseria gonorrhoeae would result in the same structure as shown for Neisseria meningitidis. The motivation to detoxify the LOS are provided previously for claim 1, as well as the reasonable expectation of success of the genetic mutation in detoxifying the LOS. Since the structure is linked to the sequence, the expectation of success of achieving this structure is the same.
Double Patenting
Nonstatutory double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
US 9687789 B2
Claim(s) 1-22, and 25-27 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 2, 10-15 of U.S. Patent No. US 9687789 B2 (hereafter referred to as Patent ‘789) in view of Chakraborti (Chakraborti et al, published 2016) and Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014).
Regarding instant claims 1-22 and 25-27, the claims of Patent ‘789 are directed to an OMV preparation from a Neisseria meningitidis bacterium with one or more mutations to decrease or knockout expression of a gene product that could include HtrB, MsbB, and rmpM.
The claims of Patent ‘789 do not explicitly claim the OMV comes from Neisseria meningitidis instead of Neisseria gonorrhoeae and do not explicitly claim the lgt mutations nor the detoxified LOS. Further, the claims of Patent ‘789 do not explicitly claim the OMVs are comprised of in an immunogenic composition or a vaccine to raise an immune response against Neisseria gonorrhoeae.
However, starting from a base OMV with LOS structures from Neisseria, as taught by Patent ‘789, the teachings, motivations, and reasonable expectation of success from combining the teachings of Chakraborti, Biemans, Zhou, and Baker to arrive at the instant invention is provided in the 35 USC 103 rejection and incorporated herein. To reconcile terminology differences because Patent ‘789 teaches mutations msbB, Biemans teaches the msbB and/or htrB genes are also called lpxL1 and lpxL2, respectively (p. 12, line 21). As evidenced by Zhou, at least lpxL1 is conserved between Neisseria meningitidis and Neisseria gonorrhoeae (Abstract). Therefore, the teachings of Biemans (and the other references, although they share a common terminology with Patent ‘789) are applicable to Patent ‘789.
In summary, one would be motivated to engineer non-phase variable epitopes to permanently prevent the epitope from evading the immune system and choose mutations that detoxify these epitope, enabling a strong immune response against the epitope, and do so by genetically engineering the specific genes in the combination shown to achieve the hexose monosaccharide pattern that is known to be an epitope for antibodies.
Claim(s) 15 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1, 2, 10-15 of U.S. Patent No. US 9687789 B2 (hereafter referred to as Patent ‘789) in view of Chakraborti (Chakraborti et al, published 2016) and Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014), as applied to claim 1 above, and further evidenced by Saha (published 2022).
The claims of Patent ‘789 do not distinctly recite the structure in instant claim 15, but the teachings, motivations, and reasons for reasonable expectation of success from combining these teachings to arrive at the instant invention with the claimed structure is provided in the 35 USC 103 rejection and incorporated herein.
US 11679149 B2
Claim(s) 1-22, and 25-27 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-5 and 8-17 of U.S. Patent No. US 11679149 B2 (hereafter referred to as Patent ‘149) in view of Chakraborti (Chakraborti et al, published 2016) and Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014).
Regarding instant claims 1-22 and 25-27, the claims of Patent ‘149 are directed to an Neisseria gonorrhoeae bacterium engineered to produce OMVs that comprise of mutations in at least one gene selected from a list including lpxL1 and lgtA, wherein genes of variable or non-protective antigens are downregulated, genes of OMP antigens are upregulated, and genes involved in making the lipid A portion of LPS (i.e. LOS) toxic downregulated. The claims are also directed to making these OMVs into a preparation and pharmaceutical composition and using this OMV preparation in a method of protecting an individual against a bacterial infection.
The claims of Patent ‘149 do not explicitly claim the exact combination of mutations or characteristics that point to these mutations.
However, starting from a base OMV with LOS structures from Neisseria gonorhoeae, as taught by Patent ‘149, the teachings, motivations, and reasonable expectation of success from combining the teachings of Chakraborti, Biemans, Zhou, and Baker to select the specific mutations to arrive at the instant invention is provided in the 35 USC 103 rejection and incorporated herein.
In summary, one would be motivated to engineer non-phase variable epitopes to permanently prevent the epitope from evading the immune system and choose mutations that detoxify these epitope, enabling a strong immune response against the epitope, and do so by genetically engineering the specific genes in the combination shown to achieve the hexose monosaccharide pattern that is known to be an epitope for antibodies.
Claim(s) 15 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-5 and 8-17 of U.S. Patent No. US 11679149 B2 (hereafter referred to as Patent ‘149) in view of Chakraborti (Chakraborti et al, published 2016) and Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014), as applied to claim 1 above, and further evidenced by Saha (published 2022).
The claims of Patent ‘149 do not distinctly recite the structure in instant claim 15, but the teachings, motivations, and reasons for reasonable expectation of success from combining these teachings to arrive at the instant invention with the claimed structure is provided in the 35 USC 103 rejection and incorporated herein.
US 12653879 B2
Claim(s) 1-22, and 25-27 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-21 of U.S. Patent No. US 12653879 B2 (hereafter referred to as Patent ‘879) in view of Chakraborti (Chakraborti et al, published 2016) and Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014).
Regarding instant claims 1-22 and 25-27, the claims of Patent ‘879 are directed to an Neisseria gonorrhoeae strain, FA1090, comprising genetic modifications that decrease or abolish expression and/or function of the lpxl1 gene and/or Lpxl1 polypeptide, and the rmp gene and/or Rmp polypeptide, and the OMV from this engineered bacterium. The claims further recite an immunogenic composition and vaccine comprising of these OMVs and a method of immunizing a subject against Neisseria using said immunogenic composition.
The claims of Patent ‘879 do not explicitly claim the exact combination of lgt gene mutations or characteristics that point to these mutations to make the LOS structure non-phase variable.
However, starting from a base OMV with LOS structures from Neisseria gonorhoeae, as taught by Patent ‘879, the teachings, motivations, and reasonable expectation of success from combining the teachings of Chakraborti, Biemans, Zhou, and Baker to select the specific mutations to arrive at the instant invention is provided in the 35 USC 103 rejection and incorporated herein.
In summary, one would be motivated to engineer non-phase variable epitopes to permanently prevent the epitope from evading the immune system and choose mutations that detoxify these epitope, enabling a strong immune response against the epitope, and do so by genetically engineering the specific genes in the combination shown to achieve the hexose monosaccharide pattern that is known to be an epitope for antibodies.
Claim(s) 15 is/are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-21 of U.S. Patent No. US 12653879 B2 (hereafter referred to as Patent ‘879) in view of Chakraborti (Chakraborti et al, published 2016) and Biemans (Biemans et al, WO 2004/015099 A2, published 02/19/2004), as evidenced by Zhou (published 2014) and Baker (published 2014), as applied to claim 1 above, and further evidenced by Saha (published 2022).
The claims of Patent ‘879 do not distinctly recite the structure in instant claim 15, but the teachings, motivations, and reasons for reasonable expectation of success from combining these teachings to arrive at the instant invention with the claimed structure is provided in the 35 USC 103 rejection and incorporated herein.
Conclusion
No claims are allowed.
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/BONIRATH CHHAY/Examiner, Art Unit 1645
Wednesday, July 22, 2026
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 30, 2026
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